EP3517537A1

EP3517537A1 - Deuterated derivative of l-tetrahydropalmatine and medical use thereof

Info

Publication number: EP3517537A1
Application number: EP17861072.1A
Authority: EP
Inventors: Bohua Zhong; Jianming Wang; Xuefeng Jin
Original assignee: Jingluweidai Information Consulting Service (beijing) Co Ltd
Current assignee: Taizhou Huayuan Medicinal Tech Co Ltd
Priority date: 2016-10-13
Filing date: 2017-09-22
Publication date: 2019-07-31
Anticipated expiration: 2037-09-22
Also published as: US10617679B2; EP3517537A4; JP7050336B2; EP3517537B1; US20190240204A1; JP2019531353A; CN107936008A; CN107936008B; WO2018068429A1

Abstract

The present disclosure relates to a compound of Formula I or a non-toxic pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, and R4 is independently selected from methyl (-CH₃) and trideuteromethyl (-CD₃), at least one of R1, R2, R3, and R4 is selected from trideuteromethyl (-CD₃).

The compound is a deuterated derivative of L-tetrahydropalmatine, which not only markedly improves pharmacological effects, but also significantly reduces cardiac side effects, liver toxicity, and remarkably decreases individual differences.

Description

FIELD OF THE INVENTION

The present disclosure relates to a novel deuterated derivative of L-tetrahydropalmatine or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound as active ingredient, and a use of the derivative or a pharmaceutically acceptable salt thereof in the preparation of psychotropic drug.

BACKGROUND OF THE INVENTION

L-tetrahydropalmatine (THP), also known as rotundine, which is an alkaloid extracted from dried tubers of the plant Corydalis, a member of the poppy family, having various therapeutic effects such as sedation, hypnosis and analgesia, clinically useful in the treatment of headache, menstrual pain and insomnia.
Recent studies have found that L-tetrahydropalmatine has better analgesic effects on neuropathic pain (NPP), inflammatory pain, cancer-induced pain and antitumor drug-induced pain. Taking L-tetrahydropalmatine for long periods of time does not lead to addiction, and has better effect on overcoming cocaine addiction, methamphetamine addiction, opioid or drug addiction, alcohol addiction, smoking addition, etc.
However, L-tetrahydropalmatine leads to cardiac side effects such as reducing blood pressure, slowing heart rate, etc. It can also cause hepatotoxicity such as elevated transaminases, etc. Moreover, great individual differences in the effects of L-tetrahydropalmatine cause the uncontrollability of safety and efficacy of drugs.
The present disclosure relates to novel deuterated derivatives of L-tetrahydropalmatine. These deuterated derivatives not only markedly improve pharmacological effects, but also significantly reduce cardiac side effects, hepatotoxicity, and remarkably decrease individual differences.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein each R1, R2, R3, and R4 is independently selected from methyl (-CH₃) and trideuteromethyl (-CD₃), at least one of R1, R2, R3, and R4 is selected from trideuteromethyl (-CD₃).
For example, the compound of Formula I or the pharmaceutically acceptable salt thereof, selected from the group consisting of compounds having the following structures:
The present disclosure also provides a pharmaceutical composition containing the compound of Formula I, for example, the compound of Formula I₁, I₂, I₃, I₄, I₅, I₆ or I₇, or a non-toxic pharmaceutically acceptable salt thereof as an active ingredient, and a suitable excipient. The pharmaceutical compositions may be solutions, tablets, capsules or injections; and the pharmaceutical compositions may be administered by injection or administered orally.
The present disclosure also provides the use of the compound of Formula I or a non-toxic pharmaceutically acceptable salt thereof in the preparation of psychotropic drug. The compound of Formula I, for example, is selected from Formula I₁, I₂, I₃, I₄, I₅, I₆ or I₇.
Furthermore, the present disclosure also provides the use of the compound of Formula I or a non-toxic pharmaceutically acceptable salt thereof in the preparation of drug for the treatment of an algesic disease, such as inflammation-induced pain, cancer-induced pain, and antitumor drug-induced pain. For example, the compound is selected from Formula I₁, I₂, I₃, I₄, I₅, I₆ or I₇.
Furthermore, the present disclosure also provides the use of the compound of Formula I or a non-toxic pharmaceutically acceptable salt thereof in the preparation of drug for the treatment of an addictive disease, such as cocaine addiction, methamphetamine addiction, opioid or drug addiction, alcohol addiction, smoking addiction, ketamine addiction. For example, the compound is selected from Formula I₁, I₂, I₃, I₄, I₅, I₆ or I₇.

EXAMPLES

The present disclosure will be further illustrated with the following examples; however, the scope of the disclosure is not limited to the examples described below. Those skilled in the art will appreciate that various changes and modifications to the examples can be made without departing from the spirit and scope of the disclosure.

Example 1 Synthesis of (13a S)-2,3,10-trimethoxy-9-[(trideutero)-methoxy]-6,8, 13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline (I₁)

341 mg (1 mmol) of (13a S)-2,3,10-trimethoxy-6,8,13,13a-tetrahydro-5H -isoquinolino[2,1-b]isoquinoline-9-ol (i-1) was added to 5 ml of dimethylform amide and dissolved under stirring; then 280 mg (2 mmol) of potassium car bonate was added, and 290 mg (2 mmol) of CD₃I was added dropwise und er stirring. The reaction mixture was stirred at 50 °C for 15 hours. The soli d was filtered off and the filtrate was evaporated to dryness under reduced pressure, and then separated by silica gel column chromatography, eluted wit h dichloromethane: methanol (10:1). The desired component was collected a nd evaporated to dryness under reduced pressure to give 130 mg of I₁. ¹H-NMR (400MHz, CDCl₃): 6.83 (s, 1H), 6.78 (d, 1H), 6.71 (d, 1H), 6.65 (s, 1H), 4.32 (d, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.81 (s, 1H), 3.59-3.50 (m, 2 H), 3.24 (dd, 1H), 3.21-3.10 (m, 2H), 2.83 (dd, 1H), 2.70-2.65 (m, 2H).

Example 2 Synthesis of (13a S)-2,3,9-trimethoxy-10-[(trideutero)-methoxy]-6,8, 13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline (I₂)

Referring to Example 1, i-1 was replaced with (13a S)-2,3,9-trimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-10-ol (i-2), which reacted with CD₃I in the presence of potassium carbonate. The obtained mixture was separated by silica gel column chromatography to give 105 mg of I₂. ¹H-NMR (400MHz, CDCl₃): 6.81 (s, 1H), 6.79 (d, 1H), 6.72 (d, 1H), 6.64 (s, 1H), 4.30 (d, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.74 (s, 1H), 3.60-3.50 (m, 2H), 3.25 (dd, 1H), 3.20-3.10 (m, 2H), 2.81 (dd, 1H), 2.71-2.65 (m, 2H).

Example 3 Synthesis of (13a S)-3,9,10-trimethoxy-2-[(trideutero)-methoxy]-6,8, 13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline (I₃)

Referring to Example 1, i-1 was replaced with (13a S)-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-2-ol (i-3), which reacted with CD₃I in the presence of potassium carbonate. The obtained mixture was separated by silica gel column chromatography to give 85 mg of I₃. ¹H-NMR (400MHz, CDCl₃): 6.86 (s, 1H), 6.79 (d, 1H), 6.75 (d, 1H), 6.68 (s, 1H), 4.35 (d, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.61 (s, 1H), 3.55-3.50 (m, 2H), 3.22 (dd, 1H), 3.08-3.10 (m, 2H), 2.84 (dd, 1H), 2.70-2.65 (m, 2H).

Example 4 Synthesis of (13a S)-2,9,10-trimethoxy-3-[(trideutero)-methoxy]-6,8, 13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline (I₄)

Referring to Example 1, i-1 was replaced with (13a S)-2,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-3-ol (i-4), which reacted with CD₃I in the presence of potassium carbonate. The obtained mixture was separated by silica gel column chromatography to give 92 mg of I₄. ¹H-NMR (400MHz, CDCl₃): 6.90 (s, 1H), 6.82 (d, 1H), 6.75 (d, 1H), 6.65 (s, 1H), 4.38 (d, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.68 (s, 1H), 3.56-3.51 (m, 2H), 3.25 (dd, 1H), 3.22-3.13 (m, 2H), 2.82 (dd, 1H), 2.71-2.68 (m, 2H).

Example 5 Synthesis of (13a S)-3,10-dimethoxy-2,9-di-[(trideutero)-methoxy]-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline (I₅)

327 mg (1 mmol) of (13a S)-3,10-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-2,9-diol (i-5) was added to 5 ml of dimethylformamide and dissolved under stirring; then 560 mg (4 mmol) of potassium carbonate was added, and 435 mg (3 mmol) of CD₃I was added dropwise under stirring. The reaction mixture was stirred at 50 °C for 15 hours. The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure, then separated by silica gel column chromatography and eluted with dichloromethane: methanol (10:1). The desired component was collected and evaporated to dryness under reduced pressure to give 115 mg of I₅. ¹H-NMR (400MHz, CDCl₃): 6.88 (s, 1H), 6.77 (d, 1H), 6.73 (d, 1H), 6.61 (s, 1H), 4.32 (d, 1H), 3.87 (s, 3H), 3.80 (s, 1H), 3.52-3.50 (m, 2H), 3.21 (dd, 1H), 3.17-3.10 (m, 2H), 2.80 (dd, 1H), 2.68-2.63 (m, 2H).

Example 6 Synthesis of (13a S)-3,9-dimethoxy-2,10-di-[(trideutero)-methoxy]-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline (I₆)

Referring to Example 5, i-5 was replaced with (13a S)-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-2,10-diol (i-6), which reacted with CD₃I in the presence of potassium carbonate. The obtained mixture was separated by silica gel column chromatography to give 100 mg of I₆. ¹H-NMR (400MHz, CDCl₃): 6.83 (s, 1H), 6.78 (d, 1H), 6.71 (d, 1H), 6.65 (s, 1H), 4.32 (d, 1H), 3.88 (s, 3H), 3.81 (s, 1H), 3.59-3.50 (m, 2H), 3.24 (dd, 1H), 3.21-3.10 (m, 2H), 2.83 (dd, 1H), 2.70-2.65 (m, 2H).

Example 7 Synthesis of (13a S)-2,3,9,10-tetra-[(trideutero)-methoxy]-6,8,13,13 a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline (I₇)

After 60g of diethylene glycol was added into in a 100mL reaction flask and stirred under nitrogen flow, 7g of potassium hydroxide was added. When the temperature was raised to 80 °C, another portion of 7g potassium hydroxide was added. After all of potassium hydroxide was dissolved and the temperature was raised to 210 °C, the water was removed. When the temperature was constant, 3.55 g (10 mmol) of L-tetrahydropalmatine was added and heated at 205-210 °C for 1.5 h. The reaction mixture was then poured into crushed ice, and neutralized to pH 8-9 with solid ammonium chloride to afford a solid precipitate. The precipitated solid was filtered, separated by silica gel column chromatography and eluted with dichloromethane: methanol (2:1). The desired component was collected and evaporated to dryness under reduced pressure to give 1.1 g of i-7.
900 mg (3 mmol) of i-7 was added to 10 ml of dimethylformamide and dissolved under stirring; then 2.0 g (15 mmol) of potassium carbonate was added, and 2.2 g (15 mmol) of CD₃I was added dropwise under stirring. The reaction mixture was stirred at 50 °C for 15 hours. The solid was filtered off and the filtrate was evaporated to dryness under reduced pressure, then separated by silica gel column chromatography and eluted with dichloromethane: methanol (10:1). The desired component was collected and evaporated to dryness under reduced pressure to give 120 mg of I₇. ¹H-NMR (400MHz, CDCl₃): 6.87 (s, 1H), 6.75 (d, 1H), 6.70 (d, 1H), 6.61 (s, 1H), 4.30 (d, 1H), 3.61-3.50 (m, 2H), 3.23 (dd, 1H), 3.17-3.05 (m, 2H), 2.81 (dd, 1H), 2.72-2.67 (m, 2H).

Example 8 Evaluation of analgesic effects of intragastrical administration in a rat formalin model

SD rats (male, weight 160-180 g) were randomly divided into groups with 6 rats in each group. After the rats were intragastrically administered different doses separately, they were placed in PVC observation boxes for habituation. After 30 min, the rats were injected subcutaneously with 20 µL of 2.7% formalin solution into the plantar surface of the left hind paws, and quickly put back in the PVC observation boxes for observation. The length of time the rats spent licking the injected-formalin paws at the early response (0-5 min, phase I) and the late response (15-30 min, Phase II) was recorded, and the analgesic activities of the test compounds were evaluated according to the length of time the rats spent licking during the period of observation. The experimental data were expressed as mean ± standard deviation. The shorter the licking time, the better the analgesic effect of the compound. The results are shown in Table 1:

Table 1 Analgesic effects of intragastric administration in a rat formalin model

Drug	Dose (mg/kg)	Reaction time for phase I (sec)	Reaction time for phase II (sec)	Drug	Dose (mg/kg)	Reaction time for phase I (sec)	Reaction time for phase II (sec)
Solvent		79.3±10.7	218.7±12.7	I₄	20	90.3±29.0	151.2±31.6
Solvent		79.3±10.7	218.7±12.7	I₄	40	61.5±36.6	74.3±38.0
THP	20	86.8±37.3	185.2±39.7	I₅	20	85.8±28.0	112.7±29.2*
THP	40	40.6±28.3*	97.5±33.6*	I₅	40	53.4±23.5*	66.5±27.6**
I₁	20	82.4±33.2	194.0±35.7	I₆	20	41.9±9.2**	66.7±8.7**
I₁	40	42.6±45.0*	92.7±25.1*	I₆	40	38.6±9.4**	40.3±9.0**
I₂	20	82.1±16.3	64.5±19.5**	I₇	20	45.2±9.9**	58.2±12.5**
I₂	40	41.0±10.7	46.5±16.0**	I₇	40	35.7±9.0**	35.9±13.6**
I₃	20	79.6±31.3	126.3±29.6
I₃	40	45.1±29.4	72.3±37.8**

Compared with solvent group, * P<0.05, ** P<0.01.

Example 9 Evaluation of analgesic effects of intragastric administration in a rat chronic sciatic nerve compression neuralgia model

SD rats (male, weight 160-180 g) were anesthetized using sodium pentobarbital (40 mg/kg), of which the sciatic nerves were separated in the middle segment of the right hind limbs. In the anterior segment of the sciatic nerve to be bifurcated, the sciatic nerve was separated from the surrounding tissue using a sterile glass hook. Four rings were loosely ligated with sterile chrome gut (No. 4, 0.15 mm in diameter) by an interval of 1 to 2 mm. Topically sprinkled with penicillin powder. The muscle tissue and skin were sutured. The rats were placed in a cage with cork dust. In the sham surgery group, the sciatic nerve was only exposed, and the other treatments were the same as described above. The rats after surgery were placed in a metal cage. The footpads of the rats were stimulated with different weights of fiber filaments with stimulus intervals of 5 seconds, until the fiber filament was found that elicits four to six foot-lifting reactions in rats during 10 stimulations. The weight of the filament was recorded and set to be the threshold (in g). Meanwhile, the number of foot-lifting response to the 10 stimulations of the fiber filaments of different weights was recorded, and the highest threshold was set at 26 g.
5-6 rats in each group were intragastrically administered and the pain thresholds were measured 1 hour after administration. Statistical analysis of the thresholds was performed using non-parametric Wilcoxon 2-Sample Test and Kruskal-Wallis Test, and the data was analyzed with SASS data processing software. $Analgesic percent (%) = (pain theshold after drug treatment - pain threshold before drug treatment) / (maximal analgesia threshold - pain thershold before drug treatment) \times % .$

The experimental results are shown in Table 2.

Table 2 Analgesic effects of intragastric administration in a rat chronic sciatic nerve compression neuralgia model

Drug	Dose (mg/kg)	Analgesic percent (%)	Drug	Dose (mg/kg)	Analgesic percent (%)
THP	20	27.41	I₅	20	39.40
THP	40	68.36	I₅	40	67.56
I₂	20	59.00	I₆	20	63.80
I₂	40	68.86	I₆	40	69.12
I₃	20	44.80	I₇	20	70.67
I₃	40	68.67	I₇	40	73.53

Example 10 Inhibition of oxycodone-induced place preference in rats

SD rats (male, weight 160-180 g) were placed in conditioned place preference (CPP) training boxes, where the partition door between the boxes was open. Time the rats spent in each of the boxes was recorded within 15 min in order to determine the natural tendency of the rats. The rats were then randomly divided into groups with 10 rats in each group according to the amount of time spent in the white box. The white box was a drug box, and the black box was a box with the absence of the drug. After intragastric administration with a test compound for 40 minutes, the rats were injected subcutaneously with oxycodone (2.5 mg/kg, s.c.) or saline, and immediately placed in the white box or the black box to be trained for 45 minutes, once a day for 9 consecutive days. On the 10th day, the rats were placed in the training boxes with the partition door open. The time the rats spent in the white box was recorded within 15 minutes to evaluate effects on place preference in the rats. The experimental results are shown in Table 3.

Table 3 Inhibition of oxycodone-induced place preference in rats

Drug	Test dose (mg/kg)	Time spent in the drug box (Mean ± S, s)
Solvent		112.11±32.23
oxycodone + saline		365.02±23.06
oxycodone + THP	10	253.23±77.14
oxycodone + THP	20	157.04±60.6**
oxycodone + I₂	10	193.94±44.3*
oxycodone + I₂	20	140.59±28.52**
oxycodone + I₆	10	183.27±33.97*
oxycodone + I₆	20	129.35±23.66**
oxycodone + I₇	10	154.32±21.38**
oxycodone + I₇	20	135.40±25.09**

Compared with solvent group, * P<0.05, ** P<0.01.

Example 11 Effects on blood pressure and heart rate in rats

SD rats (male, weight 160-180 g) were fasted for 12 hours before administration but had free access to drinking water. The rats were randomly divided into groups. They were anesthetized with an intraperitoneal injection of 50 - 60 mg/kg dose of sodium pentobarbital. Each rat was fixed on the back on the surgical table. The skin was cut from the center of the neck, and an incision of about 2.5 cm was made. The subcutaneous tissue and the median muscle were separated; the trachea was fully exposed; and the endotracheal intubation was performed. The subcutaneous tissue was separated from front to back on the right side; the right common carotid artery, the vagus nerve and the sympathetic nerve were exposed; and the carotid artery cannulation was performed. Finally, the endotracheal tube and the carotid artery cannula were respectively connected to a respiration transducer and a blood pressure transducer, and then connected to a multifunctional physiological recorder. At 30 minutes after surgery, the rats were intragastrically administrated. Heart rate and blood pressure were measured at different time points after administration. The results are shown in Tables 4 and 5, respectively.

Table 4 Effects on blood pressure in rats

Drug	Dose (mg/kg)	Blood pressure(mmHg)
Drug	Dose (mg/kg)	0	30	60	90	120	180
Solvent		114.0±11.4	112.3±10.3	109.2±8.8	109.3±9.0	118.6±12.6	115.0±10.6
THP	20	111.5±11.5	109.4±20.6	105.00±28.21	105.1±20.0	112.7±19.3	113.3±18.3
THP	40	114.2±14.6	98.0±30.1	81.63±28.8*	79.00±28.2*	91.6±24.7*	97.3±14.5
I₂	20	113.1±15.7	113.4±17.3	101.5±27.46	102.25±21.6	113.1±14.2	102.3±7.6
I₂	40	114.6±19.4	95.5±15.9*	82.5±19.8*	92.8±18.6*	110.5±15.5	100.0±17.8
I₆	20	115.6±21.9	108.5±10.75	102.0±11.4	104.7±10.70	110.5±6.8	106.5±13.7
I₆	40	111.0±21.4	95.4±14.5*	83.5±10.30*	85.2±8.0*	110.00±11.6	109.5±14.1
I₇	20	112.6±27.5	103.4±11.7	104.2±9.8	102.6±7.2	114.1±11.3	135.3±15.6
I₇	40	113.0±11.4	92.4±.10.4*	83.5±7.2*	82.6±6.5*	95.3±9.5*	101.8±8.1

Compared with solvent group, * P<0.05, ** P<0.01.

Table 5 Effects on heart rate in rats

Drug	Dose (mg/kg )	Heart rate (BTM)
Drug	Dose (mg/kg )	0	30	60	90	120	180
Solvent		407.1±34.2	401.3±32.3	409.5±31.6	406.8±20.1	398.8±28.3	412.0±22.2
THP	20	399.3±32.6	377.1±52.3	387.3±50.5	399.8±60.7	408.8±55.9	429.8±25.5
THP	40	391.8±32.9	372.1±46.5	329.0±63.2*	340.0±71.4*	372.0±64.6*	400.0±30.5
I₂	20	400.8±32.1	378.3±30.3	384.6±48.2	388.0±21.4	402.5±59.3	407.0±36.5
I₂	40	409.2±41.7	390.7±41.7	319.7±57.2*	353.8±66.7*	378.0±47.6*	407.0±42.6
I₆	20	407.1±43.4	400.2±29.4	401.0±28.47	403.0±30.2	396.7±36.3	402.5±28.8
I₆	40	414.1±37.6	375.8±29.3	362.8±20.7*	367.2±27.0*	393.5±34.6	380.8±30.5
I₇	20	401.5±32.1	380.8±33.4	389.5±26.6	405.3±31.0	391.0±24.9	398.5±28.8
I₇	40	407.9±29.5	366.8±27.7	332.6±24.9*	343.2±21.0*	356.7±25.8*	362.0±32.1

Compared with solvent group, * P<0.05, ** P<0.01.

Example 12 Evaluation of subacute toxicity

Male Wistar rats were randomly divided into groups with 10 rats in each group and weighed. A certain concentration of a test sample was ground and suspended in a 0.5% sodium carboxymethyl cellulose solution. The sodium carboxymethyl cellulose suspension containing 40 mg/kg of the test compound and a blank sodium carboxymethyl cellulose suspension as a control were intragastrically administered, once a day for 14 consecutive days. After the last administration, the rats were fasted but had free access to drinking water for 12 hours, and then anesthetized. Their blood samples were obtained from the abdominal aortas. According to SOPB093 "Standard Operating Procedures for Serum Preparation" in National Beijing Center for Drug Safety Evaluation and Research, serum was prepared for the determination of blood biochemical and immunological indicators; according to SOPB032 "Preparation of vacuum tubes with EDTA anticoagulation ", EDTA anticoagulation was prepared for the general blood routine tests.
The results showed that weight gain and food consumption in the animals in each drug group were lower than those in the solvent control group, but there was no statistical difference. The test results of 14 hematological indices and 15 biochemical blood plasma indicators showed that there was a significant increase in plasma ALT and AST in Rotundine group, I₂ and I₆ groups, and no significant difference between I₇ group and the control group in plasma ALT and AST. All other indicators were within normal ranges. The histopathological examination showed that vacuolar degeneration of hepatocytes at the peripheral and the middle zones of the hepatic lobules in Rotundine group, I₂ and I₆ groups was observed, and a small focal to a large patche of coagulative necrosis of hepatocytes occurred in the individual animals. Table 6 Effects on transaminase in rats

Dose ALT(U/L) AST(U/L)

Normal control 67.0±9.8 122.0±24.6

THP 160.0±70.6* 216.8±91.6*

I₂ 172.8±37.5* 195.0±32.1*

I₆ 165.3±38.0* 251.8±32.0*

I₇ 84.5±20.6 143.8±21.0

Compared with normal group, * P<0.05.

Claims

A compound of formula I or a pharmaceutically acceptable salt thereof:
wherein each R1, R2, R3, and R4 is independently selected from methyl (-CH₃) and trideuteromethyl (-CD₃), at least one of R1, R2, R3, and R4 is selected from trideuteromethyl (-CD₃).
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from:
A pharmaceutical composition comprising the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, and one or more suitable excipient.
A use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt or solvate thereof in the preparation of psychotropic drug.
A use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt or solvate thereof in the preparation of drug for the treatment of a algesic disease, such as inflammation-induced pain, cancer-induced pain, and antitumor drug-induced pain.
A use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt or solvate thereof in the preparation of drug for the treatment of an addictive disease, such as cocaine addiction, methamphetamine addiction, opioid or drug addiction, alcohol addiction, smoking addiction, ketamine addiction.